Protease-activated receptor 1 inhibits cholesterol efflux and promotes atherogenesis via cullin 3-mediated degradation of the ABCA1 transporter

The Journal of Biological Chemistry
Somasundaram RaghavanGadiparthi N Rao

Abstract

Although signaling of thrombin via its receptor protease-activated receptor 1 (Par1) is known to occur in atherothrombosis, its link to the actual pathogenesis of this condition is less clear. To better understand the role of thrombin-Par1 signaling in atherosclerosis, here we have studied their effects on cellular cholesterol efflux in mice. We found that by activating Par1 and cullin 3-mediated ubiquitination and degradation of ABC subfamily A member 1 (ABCA1), thrombin inhibits cholesterol efflux in both murine macrophages and smooth muscle cells. Moreover, disruption of the Par1 gene rescued ABCA1 from Western diet-induced ubiquitination and degradation and restored cholesterol efflux in apolipoprotein E-deficient (ApoE-/-) mice. Similarly, the Par1 deletion diminished diet-induced atherosclerotic lesions in the ApoE-/- mice. These observations for the first time indicate a role for thrombin-Par1 signaling in the pathogenesis of diet-induced atherosclerosis. We identify cullin 3 as a cullin-RING ubiquitin E3 ligase that mediates ABCA1 ubiquitination and degradation and thereby inhibits cholesterol efflux. Furthermore, compared with peripheral blood mononuclear cells (PBMCs) from ApoE-/- mice, the PBMCs from ApoE-/-:Par1-/- ...Continue Reading

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Citations

Dec 26, 2018·Arteriosclerosis, Thrombosis, and Vascular Biology·Jens J PosmaNigel Mackman
May 3, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Suresh GovatatiGadiparthi N Rao
Sep 26, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Megan A Slack, Scott M Gordon
Mar 17, 2019·Clinical Science·Jian YangChunyu Zeng
Dec 30, 2020·International Journal of Molecular Sciences·Lei Wang, Chaojun Tang
Mar 7, 2020·Current Medicinal Chemistry·Zhi-Xiang ZhouZhi-Sheng Jiang

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